Substituted 6,7-methylene pyrido[1,2-a]pyrimidines useful as anti-allergic and anti-ulcer agents

ABSTRACT

Substituted 6,7-methylen[1,2-a]pyrimidines and pharmaceutical compositions containing them, suitable for use as anti-allergic, anti-ulcer and anti-diabetic agents.

The present invention relates to substituted pyrido [1,2-a]pyrimidines,to a process for their preparation and to pharmaceutical compositionscontaining them.

The invention provides compounds having the following general formula##STR1## wherein A completes a bond, thereby providing a double bondbetween the 6- and 7-carbon atoms, or

A represents a --CH₂ -- to group, thereby providing a cyclopropane ringfused to the pyrido ring at the 6,7-position;

R₁ represents a hydrogen atom or a C₁ -C₁₂ alkyl group which isunsubstituted or substituted by a ##STR2## wherein each of R₄ and R₅independently represents a hydrogen atom or a C₁ -C₁₀ alkyl group, or

R₄ and R₅, taken together with the nitrogen atom to which they areattached, form a N-pyrrolidinyl, piperidino or morpholino group;

R₂ represents a hydrogen atom or a C₁ -C₆ alkyl group or a C₃ - or C₄-alkenyl group;

R₃ represents (a) a furyl, thienyl or pyridyl group each of which isunsubstituted or substituted by a methyl group; or (b) a group offormula ##STR3## wherein each of R₆, R₇ and R₈ independently representsa hydrogen or halogen atom, a hydroxy group, a C₁ -C₄ dialkylaminogroup, a group --CF₃ or a group --R₉ or --OR₉, where R₉ represents a C₁-C₆ alkyl or C₃ -- or C₄ -alkenyl group and pharmaceutically acceptablesalts thereof.

The compounds of the invention include also the pharmaceuticallyacceptable salts of the compounds of formula (I) as well as all possibleisomers (e.g. cis or trans isomers) and the mixtures thereof. Preferablythe group --CH═CH--R₃ is in the trans configuration.

The compounds in which A represents a --CH₂ -- group are hereindesignated 6,7-methylene compounds, in order to adopt a uniform systemof nomenclature based on the pyridopyrimidine fused ring system. Theycan alternatively be regarded as 1,5-diaza-4-oxo-tricyclo[5.4.0.0]undeca2,9,11-triene derivatives.

The numbering used to identify the position of the substituents in theR₃ radical is the conventional one, as is shown by the followingexamples:

(a) when R₃ is phenyl: ##STR4##

(b) when R₃ is pyridyl: ##STR5##

(c) when R₃ is furyl or thienyl: ##STR6## wherein X is oxygen orsulphur.

The expression "in particular" wherever used herein is to be interpretedas particularising the subject matter prefaced thereby as a preferenceor further preference. It is not to be understood as limiting thepreceding subject matter to the matter particularised.

The alkyl, alkenyl, alkoxy and alkenyloxy groups may be branched orstraight chain groups.

When R₁ is an unsubstituted C₁ -C₁₂ alkyl, it is preferably C₁ -C₆alkyl, preferably methyl, ethyl, isopropyl, t.-butyl or hexyl.

When R₄ and/or R₅ are C₁ -C₁₀ alkyl, the alkyl group is preferably C₁-C₄ alkyl, preferably methyl, ethyl, isopropyl or t.-butyl.

R₂ is preferably C₁ -C₄ alkyl, preferably methyl, n-propyl or n-butyl.

When R₃ is furyl, thienyl or pyridyl, it is preferably 2-furyl,2-thienyl or 2-pyridyl.

When R₉ is C₁ -C₆ alkyl, it is preferably methyl, ethyl, propyl orisopropyl. When R₉ is C₃ -C₄ alkenyl, it is preferably propenyl.Preferably R₆, R₇ and R₈ are independently selected from hydrogen,allyloxy, C₁ -C₄ alkoxy, preferably methoxy, ethoxy, n-propoxy,isopropoxy or C₁ -C₄ alkyl, preferably methyl or ethyl.

Examples of pharmaceutically acceptable salts are those with inorganicbases, e.g. sodium, potassium, calcium and aluminium salts or withorganic bases, e.g. lysine, triethylamine, triethanolamine,dibenzylamine, methylbenzylamine, di-(2-ethylhexyl)-amine, piperidine,N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine,β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamineand the other acceptable organic amines, as well as the salts withinorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and withorganic acids, e.g. citric, tartaric, maleic, malic, fumaric,methanesulphonic and ethanesulphonic acids. Preferred salts are thesodium and the potassium salts, as well as the hydrochlorides of thebasic esters, e.g. the diethylaminoethyl and dimethylaminoethyl esters.

Particularly preferred compounds of the invention are those of formula(I) wherein R₁ is (a") hydrogen; (b") C₁ -C₆ alkyl unsubstituted orsubstituted by a ##STR7## wherein each of R₄ and R₅, which are the sameor different, is C₁ -C₄ alkyl; (c") 2-(N-pyrrolidinyl)-ethyl; R₂ is C₁-C₄ alkyl; R₃ is (a"') phenyl unsubstituted or substituted by chlorineor C₁ -C₄ alkyl, in particular methyl or ethyl, or C₁ -C₄ alkoxy, inparticular methoxy, ethoxy or isopropoxy; or (b"') 2-furyl, 2-thienyl,2-pyridyl, the furyl, the thienyl and the pyridyl groups beingunsubstituted or substituted by a methyl group, as well as theirpharmaceutically acceptable salts.

In the preferred compounds of the invention the COOR₁ group is acarboxylic acid group and the compounds are free acids or carboxylicacid salts.

Examples of particularly preferred compounds of the invention are:

2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-chloro-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido-[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-thienyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-furyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-chloro-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

as well as the pharmaceutically acceptable salts thereof, in particularthe sodium salts, and the basic esters (e.g. those with2-diethylamino-ethanol and 2-dimethylamino-ethanol) and the C₁ -C₆ alkylesters thereof, in particular the methyl, ethyl, isopropyl, t-butyl andhexyl esters.

The compounds of the invention can be prepared by a process comprising:

(a) reacting a compound of the formula (II) ##STR8## wherein A, R₁ andR₂ are as defined above or a salt thereof, with an aldehyde of formula(III)

    OHC--R.sub.3                                               (III)

wherein R₃ is as defined above; or

(b) cyclopropanating a compound of formula (IV) ##STR9## wherein R₁, R₂and R₃ are as defined above, or a salt thereof, so obtaining compoundsof formula (l) wherein A is a group --CH₂ --; or

(c) hydrolyzing a compound of formula (V) ##STR10## wherein A, R₂ and R₃are as defined above and R is cyano, ##STR11## or a group ##STR12##wherein R₄ and R₅ are as defined above, and, if desired, converting acompound of formula (l) into another compound of formula (l) and/or ifdesired, converting a compound of formula (l) into a pharmaceuticallyacceptable salt and/or, if desired, converting a salt into a freecompound and/or, if desired, separating a mixture of isomers into thesingle isomers. The reaction of a compound of formula (II) with analdehyde of formula (III) is preferably carried out in the presence of abasic condensing agent such as, for example, sodium ethoxide, sodiummethoxide, sodium hydride, sodium amide, sodium hydroxide, in a solventselected, e.g., from the group consisting of methanol, ethanol,isopropanol, dioxane, water and their mixtures, at a temperaturepreferably ranging between about 0° C. and 120° C.

The cyclopropanation of a compound of formula (IV) may be carried out,for example, by reaction with dimethylsulphoxonium methylide (preparede.g. according to the method described in J. Chem. Soc., 1967, 2495),operating in an inert organic solvent selected, e.g., from the groupconsisting of dimethylformamide, dimethylsulphoxide, dioxane and theirmixtures; the temperature ranges preferably between about 0° C. andabout 50° C. and the reaction time is generally less than 5 hours,preferably less than 2 hours. Preferably 1-3 moles, in particular 1-1.5moles, of the reagent are used for one mole of the compound of formula(l).

The hydrolysis of a compound of formula (V) may be carried out byconventional methods, for example by treatment with a base such as,e.g., NaOH, KOH, LiOH, or with an organic or inorganic acid such as,e.g., H₂ SO₄, HCl, HBr, Hl, H₃ PO₄, in a solvent such as, for example,methanol, ethanol, dioxane, acetic acid, water and their mixtures, at atemperature ranging preferably from the room temperature and about 120°C. In particular, when R is the group ##STR13## the hydrolysis ispreferably carried out with an organic acid, such as formic, citric oroxalic acid in one of the above solvents or their mixtures.

A compound of formula (l) may be converted, as stated above, intoanother compound of formula (l) by known methods; for example, thecompound of formula (l) wherein --COOR₁ is an esterified carboxy group,may be converted into a compound of formula (l) wherein --COOR₁ iscarboxy by hydrolysis, e.g. basic hydrolysis, using, for example, sodiumor potassium hydroxide, in a solvent, such as, e.g., water or a loweraliphatic alcohol, and operating at a temperature ranging from the roomtemperature to about 150° C.; the same reaction may be also carried oute.g. by treatment with lithium bromide in dimethylformamide at atemperature higher than 50° C. A compound of formula (l) wherein --COOR₁is carboxy may be converted into a compound of formula (l) wherein--COOR₁ is an esterified carboxy group, e.g. a carbalkoxy groupunsubstituted or substituted by a ##STR14## wherein R₄ and R₅ are asdefined above, by conventional methods, for example by reacting thealkaline salt of the acid with the suitable alkyl halide, in an inertsolvent, such as, e.g., acetone, dioxane, dimethylformamide, orhexamethylphosphortriamide at a temperature ranging from about 0° C. toabout 100° C.

Alternatively the esterification of a compound of formula (l) may beeffected by (a') converting the compound of formula (l) wherein --COOR₁is carboxy into the corresponding halocarbonyl, preferablychlorocarbonyl, derivative, by reaction, e.g., with the desired acidhalide, for example oxalyl chloride, thionyl chloride, PCl₃, PCl₅ orPOCl₃, either in the absence of solvents or in an inert organic solventsuch as, e.g., benzene, toluene, xylene, dioxane, dichloroethane,methylene chloride, or tetrahydrofurane, at a temperature rangingpreferably from about 0° C. to about 120° C.; and then (b') reacting theobtained halocarbonyl derivative with the suitable alcohol of formula R₁--OH, wherein R₁ is as defined above, in an inert solvent such as, e.g.,benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride ortetrahydrofurane, at temperatures varying between about 0° C. and about120° C., preferably in the presence of a base, such as, e.g.,triethylamine or diethylamine. Free hydroxy groups, as substituents inR₃, may be, for example, etherified by reacting with an alkyl halide offormula R₉ X, wherein R₉ is as defined above and X is chlorine, bromineor iodine, operating in the presence of a base such as for example NaOH,KOH, Na₂ CO₃, K₂ CO₃, NaH, NaNH₂, sodium methoxide, sodium ethoxide, ina solvent selected from the group consisting, for example, of methanol,ethanol, dioxane, acetone, dimethylformamide,hexamethylphosphortriamide, tetrahydrofurane, water and their mixturesat a temperature ranging preferably between about 0° C. and about 150°C. Furthermore the etherified hydroxy groups may be converted into freehydroxy groups, for example, by treatment with pyridine hydrochloride orwith a strong acid such as, e.g., HCl, HBr, Hl, or with a Lewis acidsuch as, e.g. AlCl₃, BBr₃.

Also the optional salification of a compound of formula (l) as well asthe conversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods. For example the separation of a mixture of opticalisomers into the individual isomers may be carried out by salificationwith an optically active base and subsequent fractional crystallization.Thus, the separation of a mixture of geometric isomers may be carriedout, for example, by fractional crystallization. The compounds offormula (II) wherein A is a bond, may be, for example, preparedcyclizing a compound of formula (VI) ##STR15## wherein R₁, R₂ are asdefined above and R₁₀ is hydrogen or lower alkyl, preferably methyl orethyl.

The cyclization of a compound of formula (VI) may be, for example,carried out in the presence of an acid catalyst, such as, for example,polyphosphoric acid*, HCl, HBr, HI, sulphuric acid, p-toluenesulphonicacid, at a temperature ranging preferably between 50° C. and 250° C.;the cyclization reaction may be carried out in an inert organic solventselected, e.g., from the group consisting of a C₁ -C₆ aliphatic alcohol,dimethylformamide, dioxane, tetrahydrofuran, benzene, toluene, xylene,acetic acid, ethylene glycol monomethyl ether and their mixtures, but itis preferably carried out in the absence of a solvent.

The compounds of formula (II) wherein A is the group --CH₂ --, may beprepared, for example, by cyclopropanating a compound of formula (II)wherein A is a bond, using the same experimental conditions definedabove for the cyclopropanation of the compounds of formula (IV).

The compounds of formula (IV) may be prepared, for example, by reactinga compound of formula (II) wherein A is a bond with an aldehyde offormula (III), using the same experimental conditions as defined above.

The compounds of formula (V) may be prepared, for example, by reacting acompound of formula (VII) ##STR16## wherein A, R and R₂ are as definedabove, with an aldehyde of formula (III) using the same experimentalconditions defined above for the reaction of the latter with a compoundof formula (II).

Alternatively the compounds of formula (V) wherein A is a group --CH₂--may be prepared by cyclopropanating a compound of formula (VIII)##STR17## wherein R, R₂ and R₃ are as defined above, using the sameexperimental conditions defined above for the cyclopropanation of thecompounds of formula (IV).

The compounds of formula (VI) may be prepared, for example, by reactinga compound of formula (IX) ##STR18## wherein R₁ is as defined above,with a compound of formula (X) ##STR19## wherein R₂ and R₁₀ are asdefined above; the reaction between a compound of formula (IX) and acompound of formula (X) may be, for example, carried out using the sameexperimental conditions defined above for the cyclization of thecompounds of formula (VI). The compounds of formula (VII) wherein A is abond may be prepared, for example, cyclizing a compound of formula (XI)##STR20## wherein R, R₂ and R₁₀ are as defined above, operating in thesame experimental conditions defined above for the cyclization of thecompound of formula (VI).

The compounds of formula (VII) wherein A is a group --CH₂ -- may beprepared, for example, by cyclopropanating a compound of formula (VII)wherein A is a bond, using the same experimental conditions definedabove for the cyclopropanation of the compounds of formula (IV). Thecompounds of formula (XI) may be prepared by reacting for example, acompound of formula (XII) ##STR21## wherein R is as defined above, witha compound of formula (X), using the same experimental conditionsdefined above for the synthesis of the compounds of formula (VI). Thecompounds of formula (III), (X) and (XII) are known compounds and may beprepared by conventional methods: in some cases they are commerciallyavailable products.

The compounds of the invention have anti-allergic activity, and aretherefore useful in the prevention and treatment of all the affectionsof allergic origin, e.g. bronchial asthma, allergic rhinitis, hay fever,urticaria and dermatosis. The anti-allergic activity of the compounds ofthe invention is shown, e.g., by the fact that they are active in thepassive cutaneous anaphylaxis (PCA) test in rats, according to Goose J.and Blair A. M. J. N. (Immunology, 16, 749, 1969). An importantpeculiarity of the compounds of the invention is that they exhibit highlevels of anti-allergic activity also when administered orally.

The following table shows the activity values obtained in the PCA testin rats, after oral administration, for a number of compounds of thisinvention, identified by the codes: K 13808, FCE 20509, K 13830, FCE20099, FCE 20183, FCE 20461 and FCE 20188, in comparison with the wellknown anti-allergic drug Disodium Cromoglycate (DSCG).

The activity data are expressed in terms of K_(B) defined as the dose ofactive compound capable of reducing to one half the activity of theserum used for the sensitization: ##EQU1## wherein

B=dose of antagonist compound expressed in mg/kg;

DR=dose ratio: antilogarithm of the distance between the Log dose effectfunctions of the serum with and without antagonist (J. H. Gaddum et al,Exp. Physiol., 1955, 40, 49).

The K_(B) is adopted here because this value is independent both of thedose of the drug and the reagin concentration used for thesensitization.

The lower the K_(B) value, the higher the anti-allergic activity. In thefollowing table the compounds of the invention are identified by thecodes:

    ______________________________________                                        K 13808:                                                                              2-trans-(2-phenyl-ethenyl)-3-propyl-                                          4-oxo-4H-pyrido                                                               [1,2-a]pyrimidine-7carboxylic acid                                    K 13830:                                                                              2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-                              4-oxo-4H                                                                      pyrido[1,2-a]pyrimidine-7-carboxylic acid                             FCE 20099:                                                                            2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-                               4-oxo-4H                                                                      pyrido[1,2-a]pyrimidine-7-carboxylic acid                             FCE 20183:                                                                            2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-propyl-                              4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid                    FCE 20188:                                                                            2-trans-(2-phenyl-ethenyl)-3-propyl-6,7-methylen-                             4-oxo-4H-                                                                     pyrido[1,2-a]pyrimidine-7-carboxylic acid                             FCE 20509:                                                                            2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-                               6,7-methylen-4oxo-4H-pyrido[1,2-a]pyrimidine-                                 7-carboxylic acid                                                     FCE 20461:                                                                            2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-                          6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-                              carboxylic acid.                                                      ______________________________________                                                                   Anti-allergic                                                                 activity                                           Compound    Pretreatment time                                                                            K.sub.B (mg/kg)-p.o.                               ______________________________________                                        FCE 20188   15'            2.34                                               K 13830     15'            1.15                                               FCE 20183   15'            1.48                                               FCE 20099   15'            2.02                                               K 13808     15'            2.16                                               FCE 20509   15'            0.61                                               FCE 20461   15'            1.22                                               Disodium                                                                      Cromoglycate                                                                              15'            >200                                               ______________________________________                                    

The anti-allergic activity was determined e.g. by the inhibition of theIgE-mediated PCA according to Goose J. and Blair A. M. J. N.(Immunology, 16, 749, 1969) using homocytotropic antibodies raised inrats following the method of Mota I., Immunology, 7, 681, (1964).

The tested compounds were administered per os (p.o.) 15 minutes beforethe administration of the antigen: at least 6 rats were used for eachdose.

The compounds of the present invention furthermore possess anti-ulceractivity, as demonstrated e.g., by the fact that they proved to beactive in inhibiting stress-induced ulcers in rats undergoing restraintin a water bath at 25° C. for 40 minutes according to a modification ofthe technique described by Takagi K. and Okabe S. (Jap. J. ofPharmacology., 1968, 19:9).

In addition to the antiallergic activity, the compounds of thisinvention, in particular the compounds of formula (I) wherein R₂ ishydrogen or methyl, are useful as antidiabetic agents, as shown, forexample, by the fact that they are effective in reducing thehyperglycemic effect of glucosamine in the mouse.

In view of their high therapeutic index the compounds of the inventioncan be safely used in medicine. For example, the approximate acutetoxicity (LD50) of the compound2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido(1,2-α)pyridmidine-7-carboxylicacid in the mouse, determined with single administration of increasingdoses and measured on the seventh day of treatment is per os higher than800 mg/kg. Analogous toxicity data have been found for the othercompounds of the invention.

The compounds of the invention may be administered in conventionalmanner, for instance, in the treatment of allergies, e.g. bronchialasthma, orally and parenterally, at a daily dosage preferably of 0.5 to15 mg/kg, or by inhalation, preferably at a daily dosage of 0.5 to 100mg, preferably 0.5 to 25 mg, or by topical application (for example forthe treatment of urticaria and dermatosis), e.g., by a cream containingabout 0.5-5 mg, preferably 1-2 mg, of active principle per 100 mg ofcream. In the treatment of diabetes the compounds of the invention maybe administered orally, at a daily dosage preferably of 500 to 1000 mg.

The nature of the pharmaceutical compositions containing the compoundsof the invention in association with pharmaceutically acceptablecarriers or diluents will, of course, depend upon the therapeutical useand the desired mode of administration.

The compositions may be formulated in the conventional manner with theusual ingredients. For example, the compounds of the invention may beadministered in the form of aqueous or oily solutions or suspensions,aerosols, as well as powders, tablets, pills, gelatine capsules, syrups,drops, suppositories, or creams, or lotions for topical use.

Thus, for oral administration, the pharmaceutical compositionscontaining the compounds of this invention, are preferably tablets,pills or gelatine capsules which contain the active substance togetherwith diluents, such as, for example, lactose, dextrose, sucrose,mannitol, sorbitol, cellulose; lubricants, for instance, silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; or they may also contain binders, such as for example,starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic,tragacanth, polyvinylpyrrolidone; disintegrating agents, such as forinstance, starches, alginic acid, alginates, sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents, such asfor instance, lecithin, polysorbates, lauryl sulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

For the treatment of allergic asthma, the compounds of the invention arealso administered by inhalation. For such use, suitable compositions maycomprise a suspension or solution of the active ingredient, preferablyin the form of a salt, such as the sodium salt, in water, foradministration by means of a conventional nebulizer. Alternatively, thecompositions may comprise a suspension or a solution of the activeingredient in a conventional liquified propellant, such as,dichlorodifluoromethane or dichlorotetrafluoroethane to be administeredfrom a pressurized container, e.g. an aerosol dispenser. When themedicament is not soluble in the propellant, it may be necessary to adda co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate,and/or a surface-active agent to the composition, in order to suspendthe medicament in the propellant medium and such surface-active agentsmay be any of those commonly used for this purpose, such as non-ionicsurface-active agents, e.g. lecithin.

The compounds of the invention may also be administered in the form ofpowders by means of a suitable insufflator device and in this case thefine particle sized powders of the active ingredient may be mixed with adiluent material such as lactose.

Furthermore, the compounds of this invention may also be administered byintradermal or intravenous injection in the conventional manner.

In addition to the internal administration, the compounds of thisinvention may find use in compositions for topical application, e.g. ascreams, lotions or pastes for use in dermatological treatments. Forthese compositions the active ingredient may be mixed with conventionaloleaginous or emulsifying excipients.

The following examples illustrate but do not limit the presentinvention.

EXAMPLE 1

Methyl 6-amino-nicotinate (4g) was reacted with ethyl2-propylacetoacetate (17.3 g) in the presence of p-toluensulphonic acid(0.16 g) under stirring at 150° C. for 42 hours. After cooling anddilution with hexane the precipitate was filtered and crystallized frommethanol, thus giving 2.9 g of2-methyl-3-propyl-4-oxo-4H-pyrido[1.2-a]pyrimidine-7-carboxylic acidmethyl ester m.p. 98°-99° C., which were reacted with benzaldehyde (7 g)in methanol (100 ml), in the presence of sodium methoxide (1.78 g),under stirring at reflux temperature for 144 hours. After cooling thereaction mixture was concentrated in vacuo and diluted with ethyl ether:the precipitate was filtered, washed with ether and then dissolved inwater. After acidification with acetic acid the precipitate was filteredand washed with water until neutral: crystallization with methanol gave1.1 g of2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 250°-252° C., NMR (DMSO d6): vinylic protons δ_(H)β =7.60(d),δ_(H)α =8.05(d) p.p.m., J_(H)αHβ =16 Hz.

By preceeding analogously, starting from suitable substitutedbenzaldehydes, the following compounds were prepared:

2-trans[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 258°-259° C., NMR (CF₃ COOD): vinylic protons δ_(H)β=7.36(d), δ_(H)α =8.18(d) p.p.m., J_(H)αHβ =16 Hz;

2-trans[2-(3-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 232°-235° C.;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 245°-247° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 274°-275° C., NMR (CF₃ COOD): vinylic protons δ_(H)β=7.62(d), δ_(H)α =8.22(d) p.p.m., J_(H)αHβ =16 Hz;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 233°-236° C.;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 311°-313° C.;

2-trans-[2-(2-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 234°-235° C.;

2-trans[2-(2-isopropoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 225°-227° C.;

2-trans-[2-(2-allyloxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 218°-219° C.;

2-trans-[2-(3,4-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 275°-280° C.;

2-trans-[2-(2,4-dimethoxy-phenyl)-ethyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7)carboxylicacid;

2-trans-[2-(2-propoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 240°-242° C.;

2-trans-[2-(3-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 222°-225° C.;

2-trans-[2-(3-isopropoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 248°-249° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 205°-210° C. dec.;

2-trans-[2-(3,5-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 279°-280° C.;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 268°-270° C., NMR (CF₃ COOD): vinylic protons δ_(H)β=7.55(d), δ_(H)α =8.11(d) p.p.m., J_(H)αHβ =16 Hz;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 220°-222° C.;

2-trans-[2-(2-ethoxy-3-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 209°-211° C.;

2-trans-[2-(2,3-diethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 226°-228° C.;

2-trans-[2-(2-ethoxy-5-methoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 277°-279° C.;

2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-chloro-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-chloro-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-fluoro-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 2

By proceeding according to example 1, starting from suitable3-substituted methyl esters of2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid andbenzaldheyde, the following compounds were prepared:

2-trans-(2-phenyl-ethenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 293°-295° C., NMR (DMSO d6): vinylic protons δ_(H)β =7.18(d),δH.sub.α =8.00(d) p.p.m., J_(H)αHβ =16 Hz.

2-trans-(2-phenyl-ethenyl)-3-ethyl-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 265°-267° C., NMR (CF₃ COOD-CDCl₃): vinylic protons δ_(H)β=7.37(d), δ_(H)α =7.81(d) p.p.m., J_(H)αHβ =16 Hz;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 312°-314° C., NMR (CF₃ COOD): vinylic protons δ_(H)β=7.44(d), δ_(H)α =7.85(d) p.p.m., J_(H)αHβ =16 Hz;

2-trans-(2-phenyl-ethenyl)-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 242°-243° C., NMR (CF₃ COOD): vinylic protons δ_(H)β=7.42(d), δ_(H)α =7.84(d) p.p.m., J_(H)αH₆₂ =16 Hz;

2-trans-(2-phenyl-ethenyl)-3-trans-(propen-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 220° C. (dec.), NMR (CDCl₃ /CF₃ COOD) δ: 2.09 (b.d)(--CH═CH--CH₃), 6.53(d) (--CH═CH--CH₃), 6.66-7.03 (m) --(CH═CH--CH₃),J=16 Hz, 7.4 (d) (H.sub.β vinylic proton), 7.78 (d) (H.sub.α vinylicproton) J_(H)αHβ =16 Hz.

EXAMPLE 3

By proceeding according to Examples 1 and 2 the following compounds wereprepared:

2-trans-[2-(2-thienyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 215°-217° C.;

2-trans-[2-(5-methyl-2-thienyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-furyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-pyridyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 280°-290° C. (dec.);

2-trans-[2-(6-methyl-2-pyridyl-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2(3-pyridyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-furyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

EXAMPLE 4

By proceeding according to Examples 1, 2 and 3, starting from ethyl2-ethyl-acetoacetate and ethyl 2-butyl-acetoacetate, the followingcompounds were prepared:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 281°-282° C.;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 231°-233° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 280°-281° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 291°-292° C.;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 259°-261° C.;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 212°-214° C.;

2-trans-[2-(3-ethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 247°-249° C.;

2-trans-[2-(3-ethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 298°-300° C.;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 256°-258° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 258°-260° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 273°-275° C.;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 289°-291° C.;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans[2-(2,3-diethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans[2-(2-isopropoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans[2-(2-propoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-allyloxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 265°-268° C.;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 274°-276° C.;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 245°-247° C.;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 213°-215° C.;

2-trans-[2-(2-ethoxy-3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-3-methoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-5-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-5-methoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl)-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-thienyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-thienyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-thienyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-thienyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-pyridyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-pyridyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; p12-trans-[2-(5-methyl-2-furyl)-ethenyl]-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 5

6-amino-nicotinic acid (1.5 g) was reacted with ethyl2-methyl-acetoacetate (3.3 g) in the presence of polyphosphoric acid (15g, obtained from 7.2 g of P₂ O₅ and 7.8 g of 99% H₃ PO₄) under stirringat 100° C. for 8 hours. After cooling the reaction mixture was dilutedin ice-water and the precipitate was filtered and thoroughly washed withwater until neutral, so obtaining2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid,m.p.>280° dec.(1.8 g), which was reacted with benzaldehyde (3.5 g) inmethanol (100 ml) in the presence of sodium methoxide (2.23 g) understirring at reflux temperature for 96 hours.

After cooling the precipitate was filtered, washed with isopropyl etherand dissolved in water: acidification with acetic acid gave aprecipitate which was filtered and crystallized from dioxane to give 1.2g of2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 312°-313° C.

EXAMPLE 6

By proceeding according to Examples 1,3 and 5 starting from ethylaceto-acetate and ethyl 2-methyl-acetoacetate, the following compoundswere prepared:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 267°-269° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 272°-274° C.;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 313°-315° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 263°-265° C.;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 254°-260° C.;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 300°-304° C.;

2-trans-[2-(3-chloro-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 297°-299° C.;

2-trans-[2-(2-chloro-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>270° C., IR ν(C═O) acid 1700 cm⁻¹ ν(C═O) ketone 1675 cm⁻¹ ;

2-trans-[2-(4-chloro-phenyl)-ethenyl]-4-oxo-4H-pyrido[2,1-a]pyrimidine-7-carboxylicacid, m.p.>280° C., IR ν(C═O) acid 1710 cm⁻¹ ν(C═O) ketone 1685 cm⁻¹ ;

2-trans-[2-(2,4-dichloro-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>270° C., IR ν(C═O) acid 1715 cm⁻¹ ν(C═O) ketone 1680 cm⁻¹ ;

2-trans-[2-(2,6-dichlorophenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>265° C., IR ν(C═O) acid 1705 cm⁻¹ ν(C═O) ketone 1670 cm⁻¹ ;

2-trans-[2-(3,4-dichlorophenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 255°(dec.), IR ν(C═O)acid 1700 cm⁻¹, ν(C═O) ketone 1675 cm⁻¹;

2-trans-[2-(3-hydroxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 310°-320° C. (dec);

2-trans-[2-(4-N,N-dimethylamino-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 290°-300° C.(dec.);

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 312°-316° C.;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 219°-222° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 275°-280° C.;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 315°-319° C.;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 279°-280° C.;

2-trans-[2-(2-thienyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-furyl)-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 330°-333° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 294°-296° C.;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 306°-308° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2a-]pyrimidine-7-carboxylicacid, m.p. 270°-272° C.;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2a]pyrimidine-7-carboxylicacid; m.p. 273°-274° C.;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 305°-307° C.;

2-trans-[2-(2-chloro-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 245°(dec), IR ν(C═O) acid 1710 cm⁻¹, ν(C═O) ketone 1680, 1625cm⁻¹ ;

2-trans-[2-(3-chloro-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>280° C., IR ν(C═O) acid 1720 cm⁻¹, ν(C═O) ketone 1680, 1620cm⁻¹ ;

2-trans-[2-(4-chloro-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>280° C., IR ν(C═O) acid 1710 cm⁻¹, ν(C═O) ketone 1690, 1625cm⁻¹ ;

2-trans-[2-(2,4-dichloro-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>260° C., IR ν(C═O) acid 1710 cm⁻¹, ν(C═O) ketone 1680 cm⁻¹ ;

2-trans-[2-(2,6-dichlorophenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 252°(dec) IR ν(C═O) acid 1700 cm⁻¹, ν(C═O) ketone 1675 cm⁻¹ ;

2-trans-[2-(3,4-dichlorophenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>260° C., IR ν(C═O) acid 1705 cm⁻¹, ν(C═O) ketone 1670 cm⁻¹ ;

2-trans-[2-(3-trifluoromethyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, IR ν(C═O) acid 1720 cm⁻¹, ν(C═O) ketone 1690 cm⁻¹ ;

2-trans-[2-(3-hydroxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-hydroxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-N,N-dimethylamino-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-N,N-diethylamino-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>280° C.;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2a]pyrimidine-7-carboxylicacid, m.p. 308°-310° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 278°-279° C.;

2-trans-[2-(2,4-dimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 265°-270° C. (dec);

2-trans-[2-(3,4-dimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2a]pyrimidine-7-carboxylicacid, m.p. 308°-310° C.;

2-trans-[2-(3,5-dimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 220°-230° C. (dec);

2-trans-[2-(2-thienyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>280° C.; IR ν(C═O) acid 1705 cm⁻¹, ν(C═O) ketone 1655, 1610cm⁻¹ ;

2-trans-[2-(2-furyl)-ethenyl]-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p.>300° C., IR ν(C═O) acid 1735 cm⁻¹, ν(C═O) ketone 1655, 1615cm⁻¹.

EXAMPLE 7

Trimethyl-sulphoxonium iodide (0.7 g) was reacted with 50% sodiumhydride (0.15 g) in dimethylformamide (30 ml) under stirring at roomtemperature for 1 hour, then a solution of2-trans-(2-phenyl-ethenyl)-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid methyl ester, m.p. 214°-216° C., (0.82 g) in dimethyl-formamide (20ml) was added. The mixture was allowed to react under stirring at roomtemperature for 3 hours, then it was diluted with ice water andfiltered. Crystallization from acetone gave2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 194°-195° C. (0.58 g), which was reacted with1% KOH in 95% ethanol solution (11 ml) at reflux temperature for 15minutes. After cooling the reaction mixture was acidified with aceticacid, concentrated in vacuo and diluted with ice water: the precipitatewas filtered and washed with water until neutral. Crystallization fromacetone gave 0.34 g of2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2]pyrimidine-7-carboxylicacid, m.p. 215°-216° C., NMR (CF₃ COOD) δ: 1.22(m) and 2.93(m)(6,7-CH₂protons), 1.36(t) (CH₂ CH₃), 2.93(m)(CH₂ --CH₃), 5.51(d.d)(C-6 proton),7.01(d) (C-9 proton), 7.31(d)(H.sub.β vinyl proton), 7.63(b.s.)(phenylprotons), 7.76(d)(Hα vinyl proton), 8.26(d)(C-8 proton).

By proceeding analogously the following compounds were prepared:

2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 222°-224° C., NMR(CF₃ COOD) δ: 1.18(t) and 2.84(d.d)(6,7methylen protons), 5.44(d.d)(C-6 proton), 6.95(d)(C-9 proton),8.18(d)(C-8 proton);

2-trans-(2-phenyl-ethenyl)-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 160° C. (dec), NMR(CF₃ COOD) δ: 1.13 (t) (6,7-methylen protonand --CH₂ CH₂ CH₃), 1.60-2.00 (m) (--CH₂ CH₂ CH₃), 2.76-3.02 (m) (--CH₂CH₂ CH₃), 5.47 (d.d) (C-6 proton), 6.97 (d) (C-9 proton), 7.26 (d)(H.sub.β vinyl proton), 7.38-7.80 (m) (H.sub.α vinyl proton and phenylprotons), 8.20 (d) (C-8 proton);

2-trans-(2-phenyl-ethenyl)-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 205°-210° C. (dec.);

2-trans-(2-phenyl-ethenyl)-3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 135° C. (dec), NMR(CF₃ COOD) δ: 1.00(m)(6,7-methylen proton),2.90(m)(6,7-methylen proton and --CH₂ --CH₂ --CH₂ --CH₃), 5.66(d.d)(C-6proton), 6.95(d)(C-9 proton), 8.19(d) (C-8 proton);

2-trans-(2-phenyl-ethenyl)-3-pentyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 8

Trimethyl-sulphoxonium iodide (1 g) was reacted with 50% sodium hydride(0.22 g) in dimethylformamide (30 ml) under stirring at room temperaturefor 30 minutes, then a solution of2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 177°-179° C., (1.27 g) in dimethylformamide (20ml) was added. The mixture was allowed to react under stirring at roomtemperature for 2 hours, then it was diluted with ice water and theprecipitate was filtered, so obtaining 1.19 g of2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester (m.p. 184°-188° C.), which was treated with 0.5% KOHin 95% ethanol solution (40 ml) at reflux temperature for 15 minutes.After cooling the reaction mixture was diluted with water and acidifiedwith acetic acid and the precipitate was filtered: crystallization fromCH.sub. 2 Cl₂ /methanol gave2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (0.65 g), m.p. 184°-188° C., NMR (CF₃ COOD) δ: 1.22(d.d) (one of6,7-methylen protons), 1.36(t) (--CH₂ --CH₃), 2.96(m)(--CH₂ CH₃ and6,7-methylen proton), 4.12(s) (OCH₃), 5.50(d.d) (c-6 proton), 7.03(d)(c-9 proton), 7.36(d) (H.sub.β -vinyl proton), 7.68(d) (H.sub.α -vinylproton), 7.18-7.70 (m) (4 phenyl protons), 8.26 (d) (c-8 proton),J_(H)αHβ =16 Hz.

By proceeding analogously, the following compounds were prepared:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 225°-227° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 165° C. (dec.);

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 140° C. (dec.);

2-trans-[2-(4-fluoro-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7carboxylicacid;

2-trans-[2-(4-fluoro-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 225°-235° C. (dec.);

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 140°-150° C. (dec.);

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 208°-210° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 130° C. (dec)

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 140° C. (dec.) NMR (CF₃ COOD) δ: 1.12 (m) (6,7-methylenproton and --CH₂ CH₂ CH₃), 1.73(m) (--CH₂ CH₂ CH₃), 2.47 (s) (--CH₃),2.87 (m) (6,7-methylen proton and --CH₂ CH₂ CH₃), 5.46 (d.d) (C-6proton), 6.94 (d) (C-9 proton), 7.16 (d) (H.sub.β vinyl proton), 7.96(d) (H.sub.α -vinyl proton), 8.19 (d) (C-8 proton), J_(H)αHβ =16 Hz.

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid m.p. 130° C. (dec), NMR (CF₃ COOD) δ: 1.13 (m) (6,7-methylen protonand --CH₂ CH₂ CH₃), 2.88 (m) (6,7-methylen proton and --CH₂ CH₂ CH₃),5.46 (d.d) (C-6 proton), 6.97 (d) (C-9 proton), 7.18 (d) (H.sub.β vinylproton), 7.64 (d) (H.sub.α vinyl proton), 8.21 (d) (C-8 proton),J_(H)αHβ =16 Hz);

2-trans-[2-(3-ethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 188°-190° C.;

2-trans-[2-(3-ethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 97°-102° C. (dec.);

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 188°-190° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 100°-110° C. (dec.);

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 170°-173° C. NMR(CF₃ COOD) δ: 1.20(m)(6,7-methylene proton),2.89(m)(6,7-methylen proton and --CH₂ CH₂ CH₃), 5.48(d.d)(C-6 proton),7.00(d) (C-9 proton), 7.45(d)(Hβ vinyl proton), 7.98(d)(Hα vinylproton), 8.22(d)(C-8 proton), J_(H)αHβ =16 Hz;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 192°-195° C.;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 180°-185° C. (dec.)

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 141°-143° C.;

2-trans-[2-(2-ethoxy-3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans[2-(2-ethoxy-3-methoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid m.p. 181°-183° C.

2-trans-[2-(2-ethoxy-5-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-ethoxy-5-methoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 224°-226° C.;

2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 184°-186° C.;

2-trans-[2-(3,4-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 208°-209° C.;

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 180°-190° C. (dec.);

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 235°-237° C.;

2-trans-[2-(2-ethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 178°-180° C.;

2-trans-[2-(3,5-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 170°-180° C. (dec.);

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 150° C. (dec.);

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 205°-207° C.;

2-trans-[2-(2-methyl-phenyl)-ethenyl]3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 240° C. (dec);

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 156°-158° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 197°-198° C.;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 155°-157° C.;

2-trans-[2-(2,3-diethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 177°-179° C.

EXAMPLE 9

By proceeding according to Example 8, starting from suitable2-heteroaryl-ethenyl-derivatives, the following compounds were prepared:

2-trans-[2-(2-thienyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-thienyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 157°-162° C. (dec.);

2-trans-[2-(2-pyridyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-pyridyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-thienyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-thienyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-furyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(5-methyl-2-furyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(6-methyl-2-pyridyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 10

By proceeding according to Examples 8 and 9, starting from suitable2-aryl-ethenyl- and 2-heteroaryl-ethenyl-derivatives, the followingcompounds were prepared:

2-trans-[2(2-methyl-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 179°-182° C.;

2-trans-[2-(3-methyl-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 272°-274° C.;

2-trans-[2-(4-methyl-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 190°-194° C.;

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 150° C. (dec.);

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 204° C. (dec);

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 95°-110° C. (dec.);

2-trans-[2-(3-chloro-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 205°-210° C. (dec.);

2-trans-[2-(3-hydroxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-N,N-dimethylamino-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl-]6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 199°-202° C.;

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 195°-200° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 180°-182° C.;

2-trans-[2-(2-thienyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-furyl)-ethenyl]-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]-pyrimidine-7-carboxylicacid, m.p. 240° C. (dec.);

2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 190°-205° C. (dec.);

2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 260°-265° C. (dec.);

2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 200°-205° C. (dec.);

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 200°-205° C. (dec);

2-trans-[2-(4-methoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid; m.p. 234°-238° C.;

2-trans-[2-(2-chloro-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-chloro-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-chloro-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-hydroxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-hydroxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-N,N-dimethylamino-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(4-N,N-diethylamino-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4-dimethyl-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 220°-223° C. (dec);

2-trans-[2-(2,5-dimethyl-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 235°-240° C. (dec);

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 207°-209° C. (dec);

2-trans-[2-(2,4-dimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 171°-174° C. (dec);

2-trans-[2-(3,4-dimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 207°-210° C. (dec);

2-trans-[2-(3,4-dimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3,4-trimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,4,5-trimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3,4,5-trimethoxy-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 175°-180° C. (dec);

2-trans-[2-(2-thienyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 208°-211° C. (dec);

2-trans-[2-(2-furyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 11

2-methyl-3-propyl-7-(4,4-dimethyl-Δ²-oxazol-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine(3 g) (obtained accordingto J. Org. Chem., 1974,39, 2787) was reacted with ortho-tolualdbeide(6.3 g) in methanol (100 ml) in the presence of sodium methoxide (1.6g), under stirring at reflux temperature for 120 hours. After coolingthe reaction mixture was concentrated in vacuo and diluted with icewater: the precipitate was extracted with ethyl acetate and the solutionwas evaporated to dryness. Crystallization from methanol gave2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-7-(4,4-dimethyl-Δ.sup.2-oxazol-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, m.p. 190°-191° C., (2g), which was treated with HCl N/10 (10 ml) at room temperature for 1hour: after neutralization with NaHCO₃, the precipitate was filtered andcrystallized from methanol to give 1,1 g of2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 258°-259° C.

EXAMPLE 12

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-7-(4,4-dimethyl-Δ.sup.2-oxazol-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine (2 g), prepared accordingto Example 11, was added to a solution obtained reactingtrimethyl-sulphoxonium iodide (1.32 g) and sodium hydride (0.15 g) indimethylformamide (20 ml) for 2 hours. After 1 hour the reaction mixturewas diluted with ice water and extracted with ethyl acetate: thesolution was evaporated to dryness and the residue was crystallized fromisopropyl alcohol, so obtaining 1.1 g of2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-7-(4,4-dimethyl-Δ²-oxazol-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, m.p. 107°-108° C.,NMR(CDCl₃) δ: 0.76(t) and 2.26(d.d)(6,7-methylen protons), 4.99(d.d)(C-6 proton), 6.38(d)(C-9 proton), 7.13(d)(H.sub.β vinyl proton),8.17(d)(H.sub.α vinyl proton), J_(H)αHβ =16 Hz, which were dissolved indioxane (20 ml) and treated with a solution of oxalic acid (0.9 g) inwater (10 ml) for 90 minutes. After neutralization with NaHCO₃ anddilution with ice water the precipitate was filtered: washing withmethanol gave 0.5 g of2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 140° C. (dec.).

EXAMPLE 13

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (1,2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (12ml) at reflux temperature for 1 hour, then the mixture was evaporated todryness in vacuo. The residue was reacted with excess methanol at 50° C.for 30 minutes, then the solution was concentrated in vacuo and theresidue diluted with ice water. Filtration of the precipitate gave 1.2 gof2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine7-carboxylicacid, methyl ester, m.p. 190°-193° C. By proceeding analogously thefollowing compounds were prepared:

2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 222°-225° C.;

2-trans-(2-phenyl-ethenyl)-3-butyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 191°-193° C.;

2-trans[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 197°-198° C.

EXAMPLE 14

2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (0.8 g) was reacted with methyl iodide (0.55 g) and anhydrous K₂CO₃ (0.65 g) in dimethylformamide (7 ml) under stirring at roomtemperature for 4 hours. After dilution with ice water the precipitatewas filtered off: crystallization from acetone gave 0.5 g of2-trans-(2-phenyl-ethenyl)-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 164°-165° C.

By proceeding analogously the following compound were prepared:

2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 194°-195° C.;

2-trans-(2-phenyl-ethenyl)-3-butyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 112°-113° C.;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 190°-193° C.;

2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 164°-166° C.;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 220°-221° C.;

2-trans-[2-(2,5-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 117°-120° C.;

2-trans-[-2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, methyl ester, m.p. 143°-146° C.

EXAMPLE 15

By proceeding according to Examples 13 and 14, using ethanol or Ethyliodide resp., the following compounds were prepared:

2-trans-(2-phenyl-ethenyl)-3-propyl-4-oxo-4H-pyrido1,2-apyrimidine-7-carboxylicacid, ethyl ester;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester;

2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester, m.p. 194°-195° C.;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester, m.p. 181°-183° C.;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, ethyl ester.

EXAMPLE 16

By proceeding according to Examples 13 and 14 the isopropyl, n-hexyl andn-octyl esters of the following compounds were obtained:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 17

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (3.6 g) was reacted with 1-chloro-2-(diethylamino)ethane (2.7 g)and anhydrous K₂ CO₃ (2.8 g) in dimethylformamide (40 ml) under stirringat 50° C. for 8 hours. After dilution with water, the precipitate wasfiltered off and washed with water until neutral: crystallization fromisopropyl ether gave 2.1 g of2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-diethylamino-ethyl ester.

By proceeding analogously, the following compounds were prepared:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino)-ethyl ester.

EXAMPLE 18

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (1.2 g) was reacted with thionyl chloride (0.6 ml) in dioxane (20ml) at reflux temperature for 3 hours, then the mixture was evaporatedto dryness in vacuo. The residue was dissolved in dioxane (60 ml) andreacted with 2-(diethylamino)-ethanol (1.2 g) at room temperature for 20hours. After dilution with water the precipitate was filtered off,dissolved in acetone (100 ml) and treated with the stoichiometric amountof HCl in ether: the precipitate was filtered off, washed with ethylether and dissolved in water.

Alkalinization with K₂ CO₃, filtration and crystallization from acetonegave 0.6 g of2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino) ethyl ester, m.p. 148°-150° C.

By proceeding analogously the following compounds were prepared:

2-trans-[2-(2-methyl-phenyl)-ethyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino) ethyl ester;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino) ethyl ester.

EXAMPLE 19

Trimethyl-sulphoxonium iodide (2.3 g) was reacted with 50% sodiumhydride (0.5 g) in dimethylformamide (30 ml) under stirring at roomtemperature for 1 hour, then a solution of2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino)-ethyl ester (3.5 g) in dimethylformamide (20 ml)was added. The mixture was allowed to react under stirring at roomtemperature for 90 minutes, then it was diluted with water and extractedwith ethyl acetate: organic layer was washed with water and evaporatedto dryness in vacuo. The residue (2.9 g) was purified over a SiO₂ columnusing acetone as eluent: 1.9 g of2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, 2-(diethylamino) ethyl ester, oil, were obtained, NMR (DMSO-d6) δ:0.97 (t) ##STR22## 0.95-1.30 (m) (6,7-methylene proton and --CH₂ --CH₃),2.54 (q) ##STR23## 2.70 (t) (--O--CH₂ --CH₂ --N<), 2.4-2.8 (m)(6.7-methylen proton and --CH₂ --CH₃), 3.81 (s) (--OCH₃), 3.88 (s)(--OCH₃), 4.22 (t) (--O--CH₂ --CH₂ --N<), 4.78 (d.d) (C-6 proton), 6.38(d) (c-9 proton), 7.28 (d) (C-8 proton), 7.39 (d) (H.sub.β -vinylproton), 8.07 (H.sub.α -vinyl proton), 7.18-7.46 (m) (phenyl protons).

EXAMPLE 20

By proceeding according to Examples 17, 18 and 19 the2-dimethylaminoethyl-esters and the 2-(N-pyrrolidinyl)ethyl-esters ofthe following compounds were prepared:

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid;

2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid.

EXAMPLE 21

2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid (5 g) was reacted with NaHCO₃ (1.25 g) in water (15 ml) at 80° C.until the solution was completed. After cooling to 5° C. a precipitatewas obtained, which was filtered and washed with ice water.2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, sodium salt (3.9 g) was obtained, m.p. >300° C.

By proceeding analogously the following compounds were obtained:

2-trans-(2-phenyl-ethenyl)-3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, sodium salt, m.p. >300° C.;

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, sodium salt, m.p. >300° C.(dec.).

EXAMPLE 22

Trimethyl-sulphoxonium iodide (3.39 g) was reacted with 50% sodiumhydride (0.74 g) in dimethylformamide (70 ml) under stirring at roomtemperature for 60 minutes, then a solution of2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methylester, m.p. 130°-132° C. (3 g) in dimethylformamide (30 ml) was added.

The mixture was allowed to react under stirring at room temperature for1 hour, then it was diluted with ice water and extracted with ethylacetate.

After evaporation to dryness, the residue was crystallized fromisopropyl ether to give 1.8 g of2,3-dimethyl-6,7-methylen-4-oxo-4H-pyrido1,2-apyrimidine-7-carboxylicacid, methyl ester, m.p. 114°-116° C., which was reacted with3-chloro-benzaldehyde (2.05 g) in methanol (70 ml) in the presence ofsodium methoxide (1.1 g) under stirring at 60° C. for 24 hours. Aftercooling the reaction mixture was diluted in ice water, acidified withNaH₂ PO₄ and extracted with ethyl acetate: after evaporation in vacuo ofthe solvent, the residue was purified over SiO₂ column usingbenzene-ethylacetate-acetic acid/40:10:0.5 as eluent. After purificationwith isopropyl ether 0.32 g of2-trans-[2(3-chloro-phenyl)-ethenyl]-3-methyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, m.p. 190°-195° C. (dec), IR (C═O) acid 1710 cm⁻¹, (C═O) ketone1665 cm⁻¹.

EXAMPLE 23

Tablets, each weighing 150 mg and containing 50 mg of the activesubstance are manufactured as follows:

    ______________________________________                                        Compositions (for 10,000 tablets)                                             ______________________________________                                        2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-                           methylene-                                                                    4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid                                                       500 g                                              lactose                    710 g                                              corn starch                237,5 g                                            talc powder                37,5 g                                             magnesium stearate         15 g                                               ______________________________________                                    

2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid, lactose and a half of the corn starch are mixed; the mixture isthen forced through a sieve of 0.5 mm openings. Corn starch (18 g) issuspended in warm water (180 ml). The resulting paste is used togranulate the powder. The granules are dried, comminuted on a sieve ofsieve size 1.4 mm, then the remaining quantity of starch, talc andmagnesium stearate is added, carefully mixed, and processed into tabletsusing punches of 8 mm diameter.

EXAMPLE 24

    ______________________________________                                        Aerosol formulation:                                                          ______________________________________                                        2-trans-[2-(3-methoxy-phenyl)-ethenyl]-                                       3-ethyl-6,7-methylen-4-oxo-4H                                                 pyrido[1,2-a]pyrimidine-7-carboxylic acid                                                              2%                                                   ethanol                  10%                                                  lecithin                 0.2%                                                 mixture of dichlorofluoromethane and                                          dichlorotetrafluoromethane (70:30 mixture)                                                             ad 100%.                                             ______________________________________                                    

What we claim is:
 1. Compounds having the following general formula##STR24## wherein A represents a --CH₂ -- group, thereby providing acyclopropane ring fused to the pyrido ring at the 6,7-position;R₁represents a hydrogen atom or a C₁ -C₁₂ alkyl group which isunsubstituted or substituted by a ##STR25## wherein each of R₄ and R₅independently represents a hydrogen atom or a C₁ -C₁₀ alkyl group, or R₄and R₅, taken together with the nitrogen atom to which they areattached, form a N-pyrrolidinyl, piperidino or morpholino group; R₂represents a hydrogen atom or a C₁ -C₆ alkyl group or a C₃ - or C₄-alkenyl group; R₃ represents (a) a furyl, thienyl or pyridyl group eachof which is unsubstituted or substituted by a methyl group; or (b) agroup of formula ##STR26## wherein each of R₆, R₇ and R₈ independentlyrepresents a hydrogen or halogen atom, a hydroxy group, a C₁ -C₄dialkylamino group, a group --CF₃ or a group --R₉ or --OR₉, where R₉represents a C₁ -C₆ alkyl or C₃ - or C₄ -alkenyl group andpharmaceutically acceptable salts thereof.
 2. A compound having generalformula (I) as for claim 1 whereinR₁ is (a") hydrogen; (b") C₁ -C₆ alkylunsubstituted or substituted by a ##STR27## wherein each of R₄ and R₅,which are the same or different, is C₁ -C₄ alkyl; (c")2-(N-pyrrolidinyl)-ethyl; R₂ is C₁ -C₄ alkyl; R₃ is (a"') phenylunsubstituted or substituted by chlorine, C₁ -C₄ alkyl, or C₁ -C₄alkoxy; or (b"') 2-furyl, 2-thienyl, 2-pyridyl, the furyl, the thienyland the pyridyl groups being unsubstituted or substituted by a methylgroup, as well as their pharmaceutically acceptable salts.
 3. A compoundas claimed in claim 2 wherein R₃ is phenyl substituted by a substituentselected from the group consisting of methyl, ethyl, methoxy, ethoxy,and isopropoxy. 4.2-trans-(2-phenyl-ethenyl)-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts. 5.2-trans-(2-phenyl-ethenyl)-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts. 6.2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.7.2-trans-[2-(3-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.8.2-trans-[2-(4-methyl-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.9.2-trans-[2-(2-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.10.2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts. 11.2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.12.2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.13.2-trans-[2-(2,3-dimethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts. 14.2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-propyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.15.2-trans-[2-(2-methoxy-3-ethoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylicacid and its pharmaceutically acceptable salts, as claimed in claim 1.16. A pharmaceutical composition suitable for use as anti-allergy agent,said composition comprising a therapeutically effective amount of acompound as claimed in any one of claims 1, 2, 4-15, or 3, inassociation with a pharmaceutically acceptable carrier or diluent.
 17. Apharmaceutical composition suitable for use as an anti-ulcer agent, saidcomposition comprising a therapeutically effective amount of a compoundas claimed in any one of claims 1, 2, 4-15, or 3, in association with apharmaceutically acceptable carrier or diluent.
 18. A method ofproducing an anti-allergy effect in a patient in need of such effect,said method comprising administering to said patient and anti-allergyeffective amount of a compound as claimed in any one of claims 1, 2,4-15 or
 3. 19. A method of producing an anti-ulcer effect in a patientin need of such an effect, said method comprising administering to saidpatient an anti-ulcer effective amount of a compound as claimed in anyone of claims 1, 2, 4-15 or 3.